Previous studies in partially inbred miniature swine have demonstrated that primarily vascularized transplants across class I plus minor histocompatibility antigen differences lead to systemic tolerance in about one-third of cases without the need for exogenous immunosuppression. Based on the hypothesis that tolerance induction in these situations may involve a limitation of T-cell help at the time of first antigen exposure, we have recently evaluated the effect of a brief course of Cyclosporin A immediately following renal allografts in this model. Such treatment increased the percentage of class I plus minor antigen mismatched transplant recipients that develop long-term tolerance to 100%. The major goals of this proposal are to study the early immunologic parameters which lead to tolerance induction in this experimental system and to examine the applicability of these findings to additional organs (heart) and species (primate) as a prelude to future clinical applications. Specifically, we shall: 1) Investigate the role of an active immune process in generating tolerance following class I mismatched renal transplants; 2) Study the cell populations present in the graft at critical times following transplantation by histology, by cell culture analysis and by patterns of cytokine gene expression: 3) Examine the basis of differences in the immune response to cardiac versus renal allografts in this model and determine whether or not our findings can be extended to cardiac transplants; and 4) Perform renal transplants between pairs of MLR-negative cynomolgus monkeys with or without a brief course of immunosuppression aimed at elimination of T cell help. These studies should provide valuable insight into the mechanism by which tolerance to a primarily vascularized transplant is induced. In addition, if the cynomolgus monkey studies are successful, a similar clinical protocol for HLA matched organ transplants is envisioned in the future. Although rodent models have been of great importance to studies of transplantation, it has proved much more difficult to induce specific transplantation tolerance in man than in rodents. Of possible relevance to these studies is the difference in expression of class II MHC antigens on vascular endothelium between rodents and large animals. For preclinical studies on the induction of tolerance across selected MHC barriers it is therefore important to utilize a large animal model.